5-ethylimidarotriazones

ABSTRACT

The invention relates to novel 5-ethyl-imidazotriazinones, processes for their preparation and their use in medicaments, esp. for the treatment and/or prophylaxis of inflammatory processes and/or immune diseases.

The invention relates to novel 5-ethyl-imidazotriazinones, processes fortheir preparation and their use in medicaments, esp. for the treatmentand/or prophylaxis of inflammatory processes and/or immune diseases.

Phosphodiesterases (PDEs) are a family of enzymes responsible for themetabolism of the intracellular second messengers cAMP (cyclic adenosinemonophosphate) and cGMP (cyclic guanosine monophosphate). PDE 4, as acAMP specific PDE, catalyses the conversion of cAMP to AMP and is themajor if not sole isoform of the phosphodiesterase enzymes present ininflammatory and immune cell types. Inhibition of this enzyme leads tothe accumulation of cAMP which, in these cells, leads to the inhibitionof a range of pro-inflammatory functions. Uncontrolled production ofinflammatory mediators can lead to acute and chronic inflammation,tissue damage, multi-organ failures and to death. Additionally,elevation of phagocyte cAMP leads to inhibition of oxygen radicalproduction. This cell function is more sensitive than others such asaggregation or enzyme release.

It is now recognised that both asthma and COPD (Chronic obstructivepulmonary disease) are chronic inflammatory lung diseases. In the caseof asthma the eosinophil is the predominant infiltrating cell.Subsequent release of superoxide radicals as well as damaging cationicproteins from these infiltrating cells are believed to play a role inthe progression of the disease and development of airwayhyperreactivity.

By contrast, in COPD the neutrophil is the predominant inflammatory celltype found in the lungs of sufferers. The action of mediators andproteases released in the environment of the lung is believed to resultin the irreversible airway obstruction seen in COPD. In particular theaction of proteases in degrading the lung matrix results in feweralveoli and is likely to be the major cause of accelerated long termlung function decline seen in this disease.

Treatment with a PDE 4 inhibitor is expected to reduce the inflammatorycell burden in the lung in both of these diseases [M. S. Barnette, “PDE4 inhibitors in asthma and chronic obstructive pulmonary disease”, in:Progress in Drug Research, Birkhäuser Verlag, Basel, 1999, pp. 193–229;H. J. Dyke and J. G. Montana, “The therapeutic potential of PDE 4inhibitors”, Exp. Opin. Invest. Drugs 8, 1301–1325 (1999)].

WO 99/24433 and WO 99/67244 describe 2-phenyl-imidazotriazinones assynthetic intermediates for the synthesis of2-(aminosulfonyl-phenyl)-imidazotriazinones as inhibitors ofcGMP-metabolizing phosphodiesterases.

U.S. Pat. No. 4,278,673 discloses 2-aryl-imidazotriazinones withcAMP-phosphodiesterase inhibitory activity for the treatment of i.a.asthma.

The present invention relates to compounds of the general formula (I)

-   -   in which    -   A denotes phenylene or pyridinylene, which can be substituted by        0 to 3 residues selected independently from the group consisting        of halogen, (C₁–C₄)-alkyl, trifluoromethyl, cyano, nitro,        (C₁–C₄)-alkoxy and trifluoromethoxy,    -   R¹ denotes hydroxy or a group of the formula —NR³R⁴,        —X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein        -   X denotes a bond, —CH₂—, —CH₂—CH₂— or —CH═CH—,        -   R³ and R⁴ are independently selected from the group            consisting of hydrogen, (C₁–C₆)-alkyl, (C₃–C₇)-cycloalkyl,            (C₁–C₆)-alkanoyl and (C₆–C₁₀)-aroyl, wherein (C₁–C₆)-alkyl            can be further substituted with 0 to 3 substituents selected            independently from the group consisting of            (C₃–C₇)-cycloalkyl and (C₆–C₁₀)-aryl,        -   R⁵ denotes hydrogen or (C₁–C₆)-alkyl,        -   R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, (C₁–C₆)-alkyl, (C₃–C₇)-cycloalkyl            and (C₆–C₁₀)-aryl, or together with the nitrogen atom to            which they are attached form a 4- to 7-membered heterocyclic            ring which may contain one additional ring heteroatom            selected from N, O or S,    -   R² denotes (C₃–C₁₀)-cycloalkyl, which is optionally substituted        up to two times by residues selected independently from the        group consisting of (C₁–C₆)-alkyl, (C₁–C₆)-alkoxy, hydroxy,        halogen, trifluoromethyl and oxo.

The compounds according to the invention can also be present in the formof their salts, solvates or solvates of the salts.

Depending on their structure, the compounds according to the inventioncan exist in stereoisomeric forms (enantiomers, diastereomers). Theinvention therefore relates to the enantiomers or diastereomers and totheir respective mixtures. Such mixtures of enantiomers and/ordiastereomers can be separated into stereoisomerically unitaryconstituents in a known manner.

The invention also relates to tautomers of the compounds, depending onthe structure of the compounds.

Salts for the purposes of the invention are preferably physiologicallyacceptable salts of the compounds according to the invention.

Physiologically acceptable salts of the compounds (I) include acidaddition salts of mineral acids, carboxylic acids and sulphonic acids,for example salts of hydrochloric acid, hydrobromic acid, sulphuricacid, phosphoric acid, methanesulphonic acid, ethanesulphonic acid,toluenesulphonic acid, benzenesulphonic acid, naphthalene-disulphonicacid, acetic acid, propionic acid, lactic acid, tartaric acid, malicacid, citric acid, fumaric acid, maleic acid and benzoic acid.

Physiologically acceptable salts of the compounds (I) also include saltsof customary bases, such as for example and preferably alkali metalsalts (for example sodium and potassium salts, alkaline earth metalsalts (for example calcium and magnesium salts) and ammonium saltsderived from ammonia or organic amines having 1 to 16 carbon atoms, suchas illustratively and preferably ethylamine, diethylamine,triethylamine, ethyldiisopropylamine, monoethanolamine, diethanolamine,triethanolamine, dicyclohexylamine, dimethylaminoethanol, procaine,dibenzylamine, N-methylmorpholine, dihydroabietylamine, arginine,lysine, ethylenediamine and methylpiperidine.

Solvates for the purposes of the invention are those forms of thecompounds that coordinate with solvent molecules to form a complex inthe solid or liquid state. Hydrates are a specific form of solvates,where the coordination is with water.

For the purposes of the present invention, the substituents have thefollowing meanings, unless otherwise specified:

Alkyl per se and “alk” and “alkyl” in alkoxy, alkanoyl represent alinear or branched alkyl radical having generally 1 to 6, preferably 1to 4 and particularly preferably 1 to 3 carbon atoms, representingillustratively and preferably methyl, ethyl, n-propyl, isopropyl,tert-butyl, n-pentyl and n-hexyl.

Alkoxy illustratively and preferably represents methoxy, ethoxy,n-propoxy, isopropoxy, tert-butoxy, n-pentoxy and n-hexoxy.

Alkanoyl illustratively and preferably represents acetyl and propanoyl.

Aroyl illustratively and preferably represents benzoyl.

Cycloalkyl represents a cycloalkyl group having generally 3 to 7 andpreferably 5 to 6 carbon atoms, illustratively and preferablyrepresenting cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl andcycloheptyl.

Aryl per se and in arylamino and in arylcarbonyl represents a mono- totricyclic aromatic carbocyclic radical having generally 6 to 10 carbonatoms, illustratively and preferably representing phenyl.

Halogen represents fluorine, chlorine, bromine and iodine.

A preferred embodiment of the invention relates to compounds of thegeneral formula (I), in which

-   -   A denotes 1,3- or 1,4-phenylene, which can be substituted by 0        to 3 residues selected independently from the group consisting        of fluoro, chloro, bromo, methyl, trifluoromethyl, methoxy,        ethoxy and trifluoromethoxy,    -   R¹ denotes hydroxy or a group of the formula —NR³R⁴,        —X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein        -   X denotes a bond, —CH₂—CH₂— or —CH═CH—,        -   R³ denotes hydrogen,        -   R⁴ denotes hydrogen, (C₁–C₄)-alkyl or (C₁–C₅)-alkanoyl,            wherein (C₁–C₄)-alkyl can be further substituted with 0 to 3            substituents selected independently from the group            consisting of cyclopentyl, cyclohexyl or phenyl,        -   R⁵ denotes hydrogen,        -   R⁶ and R⁷ are independently selected from the group            consisting of hydrogen, (C₁–C₄)-alkyl and            (C₅–C₆)-cycloalkyl, or together with the nitrogen atom to            which they are attached form a 5- to 6-membered heterocyclic            ring which may contain one additional ring heteroatom            selected from N, O or S,    -   R² denotes (C₄–C₇)-cycloalkyl, which is optionally substituted        up to two times by residues independently selected from the        group consisting of (C₁–C₄)-alkyl, (C₁–C₄)-alkoxy, hydroxy,        fluoro, trifluoromethyl and oxo.

Another preferred embodiment of the invention relates to compounds ofthe general formula (I), in which

-   -   A denotes 1,3- or 1,4-phenylene,    -   R¹ denotes hydroxy or a group of the formula —NR³R⁴,        —X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein        -   X denotes a bond,        -   R³ denotes hydrogen,        -   R⁴ denotes hydrogen, (C₁–C₄)-alkyl, (C₁–C₅)-alkanoyl,            cyclohexyl methyl or benzyl,        -   R⁵ denotes hydrogen,        -   R⁶ denotes hydrogen, methyl or ethyl,        -   R⁷ denotes hydrogen, (C₁–C₄)-alkyl, cyclopentyl or            cyclohexyl, or        -   R⁶ and R⁷ together with the nitrogen atom to which they are            attached form a morpholino or piperidino ring,    -   R² denotes (C₄–C₆)-cycloalkyl, which is optionally substituted        up to two times by identical or different (C₁–C₄)-alkyl        residues.

Another preferred embodiment of the invention relates to compounds ofthe general formula (I), in which

-   -   R¹ and A have the meaning indicated in claim 3,    -   R² denotes cyclobutyl, cyclopentyl or        cis-4-tert-butyl-cyclohexyl.

The invention furthermore provides a process for preparing the compoundsof the general formula (I) according to the invention, characterized inthat

-   compounds of the general formula (II)

-   in which-   R² is as defined above-   and-   L represents straight-chain or branched alkyl having up to 4 carbon    atoms,-   are condensed with compounds of the general formula (III)

-   in which-   A and R¹ are as defined above,-   preferably using ethanol as a solvent, to the compounds of the    general formula (IV)

-   in which-   A, R¹ and R² are as defined above,-   which can optionally after isolation be reacted with a dehydrating    agent, preferably phosphorous oxytrichloride, to yield the compounds    of the general formula (I).

The compounds of the general formula (IV) can alternatively be preparedby

-   [A] condensation of compounds of the general formula (IIa)

-   -   in which    -   L is as defined above,    -   with compounds of the general formula (III) to compounds of the        general formula (IVa)

-   -   in which    -   A and R¹ are as defined above,    -   preferably using ethanol as a solvent,

-   [B] followed by hydrolysis of the compounds of the general formula    (IVa) to compounds of the general formula (V)

-   -   in which    -   A and R¹ are as defined above,

-   [C] and finally by condensation of the compounds of the general    formula (V) with compounds of the general formula (VI)

-   -   in which    -   R² is as defined above, and    -   T represents a leaving group, preferably chlorine.

The process according to the invention can be illustrated using thefollowing scheme as an example:

Solvents which are suitable for the individual steps are the customaryorganic solvents which do not change under the reaction conditions.These preferably include ethers, such as diethyl ether, dioxan,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethane, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide, acetonitrile, acetone, or pyridine. It isalso possible to use mixtures of the above-mentioned solvents.Particular preference is given to ethanol for the reaction(II)/(IIa)+(III)→(IV)/(IVa), and dichloroethane for the cyclisation(IV)→(I).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

The process steps according to the invention are generally carried outunder atmospheric pressure. However, it is also possible to operateunder super atmospheric pressure or under reduced pressure (for example,in a range from 0.5 to 5 bar).

The compounds of the general formula (IVa) are preferably hydrolysed tocompounds of the general formula (V) under acidic conditions as forexample in refluxing 2N hydrochloric acid.

The compounds of the general formula (V) are condensed with thecompounds of the general formula (VI) to compounds of the generalformula (IV) in inert solvents, if appropriate in the presence of abase.

Suitable inert solvents are the customary organic solvents which do notchange under the reaction conditions. These preferably include ethers,such as diethyl ether, dioxan, tetrahydrofuran, glycol dimethyl ether,or hydrocarbons, such as benzene, toluene, xylene, hexane, cyclohexaneor mineral oil fractions, or halogenated hydrocarbons, such asdichloromethane, trichloromethane, carbon tetrachloride,dichloroethylene, trichloroethylene or chlorobenzene, or ethyl acetate,dimethylformamide, dimethylsulfoxide, hexamethylphosphoric triamide,acetonitrile, acetone, or pyridine. It is also possible to use mixturesof the above-mentioned solvents.

Suitable bases are generally alkali metal hydrides or alkali metalalkoxides, such as, for example, sodium hydride or potassiumtert-butoxide, or cyclic amines, such as, for example, piperidine,pyridine, 4-N,N-dimethylaminopyridine or (C₁–C₄)-alkylamines, such as,for example, triethylamine. Preference is given to triethylamine,pyridine and/or 4-N,N-dimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (V).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from ° C. to 100° C.

Some of the compounds of the general formula (II) are known, or they arenovel, and they can then be prepared by

-   converting compounds of the general formula (VI)

-   in which-   R² is as defined above, and-   T represents a leaving group, preferably chlorine,-   initially by reaction with α-aminobutyric acid in inert solvents, if    appropriate in the presence of a base and trimethylsilyl chloride,    into the compounds of the general formula (VII)

-   in which-   R² is as defined above,-   and finally reacting with the compound of the formula (VII)

-   in which-   L is as defined above,-   in inert solvents, if appropriate in the presence of a base.

The compounds of the general formula (IIa) can be prepared analogously.

Suitable solvents for the individual steps of the process are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxan, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide, acetonitrile, acetone, or pyridine. It isalso possible to use mixtures of the above-mentioned solvents.Particular preference is given to dichloromethane for the first step andto a mixture of tetrahydrofuran and pyridine for the second step.

Suitable bases are generally alkali metal hydrides or alkali metalalkoxides, such as, for example, sodium hydride or potassiumtert-butoxide, or cyclic amines, such as, for example, piperidine,pyridine, 4-N,N-dimethylaminopyridine or (C₁–C₄)-alkyl-amines, such as,for example, triethylamine. Preference is given to triethylamine,pyridine and/or 4-N,N-dimethylaminopyridine.

The base is generally employed in an amount of from 1 mol to 4 mol,preferably from 1.2 mol to 3 mol, in each case based on 1 mol of thecompound of the formula (VII).

The reaction temperature can generally be varied within a relativelywide range. In general, the reaction is carried out in a range of from−20° C. to 200° C., preferably of from 0° C. to 100° C.

The compounds of the general formulae (VI) and (VIII) are known per se,or they can be prepared by customary methods.

The compounds of the general formula (III) are known or can be preparedby

-   reacting compounds of the general formula (IX)

-   in which-   A and R¹ are as defined above, and-   Y represents a cyano, carboxyl, methoxycarbonyl or ethoxycarbonyl    group,    with ammonium chloride in toluene and in the presence of    trimethylaluminium in hexane in a temperature range from −20° C. to    room temperature, preferably at 0° C. and atmospheric pressure, and    reacting the resulting amidine, if appropriate in situ, with    hydrazine hydrate.

The compounds of the general formula (IX) are known per se, or they canbe prepared by customary methods.

-   [A] Alternatively, compounds of the general formula (I), wherein A    is phenyl and R¹ is amino, can be prepared by reduction of compounds    (X)

-   wherein-   R² has the meaning indicated above, and R¹⁻¹ represents nitro,    preferably with palladium on charcoal and hydrogen.

Suitable inert solvents for the reduction are the customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers, such as diethyl ether, dioxan,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide, acetonitrile, acetone, or pyridine. It isalso possible to use mixtures of the above-mentioned solvents. Preferredis tetrahydrofuran.

The free amines yielded by this reduction can successively be convertedto other amino derivatives, e.g by reductive amination with carbonylderivatives in the presence of cyanoborohydride (yielding secondaryamines), or by reaction with acylating agents such as acid chlorides(yielding amides).

-   [B] Alternatively, compounds of the general formula (I), wherein A    is phenyl and R¹ is aminocarbonyl or carboxyl, can be prepared by    saponification of compounds (X), wherein R² has the meaning    indicated above, and R¹⁻¹ represents cyano, preferably with    potassium carbonate and hydrogen peroxide.

Suitable inert solvents for the reduction are the customary organicsolvents which do not change under the reaction conditions. Thesepreferably include ethers, such as diethyl ether, dioxan,tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene, or ethyl acetate, dimethylformamide, dimethylsulfoxide,hexamethylphosphoric triamide, acetonitrile, acetone, or pyridine. It isalso possible to use mixtures of the above-mentioned solvents. Preferredis ethanol/water.

The amides or carboxylic acids yielded by this saponification cansuccessively be converted to other carbonyl derivatives by standardprocedures, e.g. amide coupling or esterification.

-   [C] Alternatively, compounds of the general formula (I), wherein A    is phenyl and R¹ is —X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein X    denotes —CH═CH— and R⁵, R⁶ and R⁷ are as described above, can be    prepared by coupling of compounds (X), wherein R² has the meaning    indicated above, and R¹⁻¹ representsbromo, with the respective    acrylic acid derivatives.

This coupling preferably takes place in the presence ofdichlorobis(triphenyl-phosphine)palladium(II) and a base, e.g.triethylamine. The acrylic acid derivatives yielded by this coupling cansuccessively be converted to other derivatives, e.g. by hydrogenation ofthe double bond.

Compounds of the general formula (X) can be prepared by reaction ofcompounds of the general formula (Va)

-   with compounds of the general formula (VI) in the presence of    phosphoroxychloride.

Suitable inert solvents for the reaction with carbonyl compounds are thecustomary organic solvents which do not change under the reactionconditions. These preferably include ethers, such as diethyl ether,dioxan, tetrahydrofuran, glycol dimethyl ether, or hydrocarbons, such asbenzene, toluene, xylene, hexane, cyclohexane or mineral oil fractions,or halogenated hydrocarbons, such as dichloromethane, trichloromethane,carbon tetrachloride, dichloroethylene, trichloroethylene orchlorobenzene. It is also possible to use mixtures of theabove-mentioned solvents. Preferred is dichloroethane.

Compounds of the general formula (Va) are compounds of the generalformula (V), wherein A represents phenyl and R¹ represents a nitro,cyano or bromo group. They can be prepared analogously to compounds ofthe general formula (V).

The compounds of the general formula (I) inhibit the PDE 4 resident inthe membranes of human neutrophils. One measured functional consequenceof this inhibition was inhibition of superoxide anion production bystimulated human neutrophils.

The compounds of the general formula (I) can therefore be employed inmedicaments for the treatment of inflammatory processes, esp. acute andchronic inflammatory processes, and/or immune diseases.

The compounds according to the invention are preferably suitable for thetreatment and prevention of inflammatory processes, i.e. acute andchronic inflammatory processes, and/or immune diseases, such asemphysema, alveolitis, shock lung, all kinds of chronic obstructivepulmonary diseases (COPD), adult respiratory distress syndrome (ARDS),asthma, bronchitis, cystic fibrosis, eosinophilic granuloma,arteriosclerosis, arthrosis, inflammation of the gastro-intestinaltract, myocarditis, bone resorption diseases, reperfusion injury,Crohn's disease, ulcerative colitis, systemic lupus erythematosus, typeI diabetes mellitus, psoriasis, anaphylactoid purpura nephritis, chronicglomerulonephritis, inflammatory bowel disease, atopic dermatitis, otherbenign and malignant proliferative skin diseases, allergic rhinitis,allergic conjunctivitis, vernal conjunctivitis, arterial restenosis,sepsis and septic shock, toxic shock syndrome, grafts vs. host reaction,allograft rejection, treatment of cytokine-mediated chronic tissuedegeneration, rheumatoid arthritis, arthritis, rheumatoid spondylitis,osteoahritis, coronary insufficiency, myalgias, multiple sclerosis,malaria, AIDS, cachexia, prevention of tumor growth and tissue invasion,leukemia, depression, memory impairment and acute stroke. The compoundsaccording to the invention are additionally suitable for reducing thedamage to infarct tissue after reoxygenation.

The active component can act systemically and/or locally. For thispurpose, it can be applied in a suitable manner, for example orally,parenterally, pulmonally, nasally, sublingually, lingually, buccally,rectally, transdermally, conjunctivally, otically or as an implant.

For these application routes, the active component can be administeredin suitable application forms.

Useful oral application forms include application forms which releasethe active component rapidly and/or in modified form, such as forexample tablets (non-coated and coated tablets, for example with anenteric coating), capsules, sugar-coated tablets, granules, pellets,powders, emulsions, suspensions, solutions and aerosols.

Parenteral application can be carried out with avoidance of anabsorption step (intravenously, intraarterially, intracardially,intraspinally or intralumbarly) or with inclusion of an absorption(intramuscularly, subcutaneously, intracutaneously, percutaneously orintraperitoneally). Useful parenteral application forms includeinjection and infusion preparations in the form of solutions,suspensions, emulsions, lyophilisates and sterile powders.

Forms suitable for other application routes include for exampleinhalatory pharmaceutical forms (including powder inhalers, nebulizers),nasal drops/solutions, sprays; tablets or capsules to be administeredlingually, sublingually or buccally, suppositories, ear and eyepreparations, vaginal capsules, aqueous suspensions (lotions, shakemixtures), lipophilic suspensions, ointments, creams, milk, pastes,dusting powders or implants.

The active components can be converted into the recited applicationforms in a manner known per se. This is carried out using inertnon-toxic, pharmaceutically suitable excipients. These include interalia carriers (for example microcrystalline cellulose), solvents (forexample liquid polyethylene glycols), emulsifiers (for example sodiumdodecyl sulphate), dispersing agents (for example polyvinylpyrrolidone),synthetic and natural biopolymers (for example albumin), stabilizers(for example antioxidants such as ascorbic acid), colorants (for exampleinorganic pigments such as iron oxides) or taste and/or odor corrigents.

Generally it has proved advantageous in the case of parenteralapplication to administer amounts of about 0.001 to 1 mg/kg andpreferably about 0.01 to 0.5 mg/kg of body weight to achieve efficaciousresults. In the case of oral administration, the amount is about 0.001to 50 mg/kg and preferably about 0.001 to 20 mg/kg of body weight.

In spite of this, it can be necessary in certain circumstances to departfrom the amounts mentioned, namely as a function of body weight,application route, individual behaviour towards the active component,manner of preparation and time or interval at which application takesplace. It can for instance be sufficient in some cases to use less thanthe aforementioned minimum amount, while in other cases the upper limitmentioned will have to be exceeded. In the case of the application oflarger amounts, it can be advisable to divide them into a plurality ofindividual doses spread through the day.

The percentages in the tests and examples which follows are, unlessotherwise stated, by weight; parts are by weight. Solvent ratios,dilution ratios and concentrations reported for liquid/liquid solutionsare each based on the volume.

Test Descriptions

-   1. Preparation of human PMN    -   Human PMN (polymorphonuclear neutrophil leucocytes) are readily        purified from peripheral blood. Phosphodiesterase in these cells        is predominantly located in the membrane fraction. Inhibitory        potency of compounds against this preparation correlate well        with the anti-inflammatory activity as measured by inhibiton of        superoxide production.    -   Blood was taken from healthy subjects by venous puncture and        neutrophils were purified by dextran sedimentation and density        gradient centrifugation on Ficoll Histopaque and resuspended in        the buffered medium.-   2. Assay of human PMN phosphodiesterase    -   This was performed as a particulate fraction from human PMN        essentially as described by Souness and Scott [Biochem. J. 291,        389–395 (1993)]. Particulate fractions were treated with sodium        vanadate/glutathione as described by the authors to express the        discrete stereospecific site on the phosphodiesterase enzyme.        The prototypical PDE 4 inhibitor, rolipram, had an IC₅₀ value in        the range 450 nM–1500 nM, thus defining this preparation as the        so-called “low affinity” [L] form. The preparation examples had        IC₅₀ values within the range of 1 nM–1,000 nM.-   3. Inhibition of FMLP-stimulated production of superoxide radical    anions    -   Neutrophils (2.5×10⁵ ml⁻¹) were mixed with cytochrome C (1.2        mg/ml) in the wells of a microtitre plate. Compounds according        to the invention were added in dimethyl sulphoxide (DMSO).        Compound concentration ranged from 2.5 nM to 10 μM, the DMSO        concentration was 0.1% v/v in all wells. After addition of        cytochalasin b (5 μg×ml⁻¹) the plate was incubated for 5 min at        37° C. Neutrophils were then stimulated by addition of 4×10⁻⁸ M        FMLP (N-Formyl-Met-Leu-Phe) and superoxide generation measured        as superoxide dismutase inhibitable reduction of cytochrome C by        monitoring the OD₅₅₀ in a Thermomax microtitre plate        spectrophotometer. Initial rates were calculated using a Softmax        kinetic calculation programme. Blank wells contained 200 units        of superoxide dismutase.    -   The inhibition of superoxide production was calculated as        follows:

$\frac{\left\lbrack {1 - \left( {{Rx} - {Rb}} \right)} \right\rbrack}{\left( {{Ro} - {Rb}} \right)} \times 100$

-   -   Rx=Rate of the well containing the compound according to the        invention    -   Ro=Rate in the control well    -   Rb=Rate in the superoxide dismutase containing blank well

-   4. Assay of binding to the rolipram binding site (PDE 4 high    affinity site; “H-PDE 4 form”) in rat brain membranes:    -   The activity of compounds on the PDE 4 high affinity site        (“H-PDE 4 form”) is readily measured by determining their        potency for displacement of [³H]-rolipram from its binding site        in rat brain membranes. Activity at this site is believed to be        a measure of side effect potential (e.g. stimulation of stomach        acid secretion, nausea and emesis).    -   The rolipram binding site assay was performed essentially as        described by Schneider et al. [Eur. J. Pharmacol. 127, 105–115        (1986)].

-   5. Lipopolysaccharide (LPS)—induced neutrophil influx into rat lung    -   Intranasal administration of LPS to rats causes a marked influx        of neutrophils into the lungs measurable by histological or        biochemical (myeloperoxidase content of the cell pellet)        analysis of the bronchoalveolar lavage fluid 24 h later. Rats        were treated with test compound or vehicle administered by the        oral route 1 h prior to and 6 h after administration of        intranasal LPS. 24 hours later animals were euthanatized and        their lungs lavaged with PBS (phosphate buffered saline).        Neutrophil and total cell numbers were analysed.

-   6. Emetic potential in the marmoset    -   Vehicle or test compound was administered by the oral route to        conscious marmosets. Animals were observed for emetic episodes        or abnormal behaviour for 1 h post dosing. In some experiments,        if no adverse response was seen, a separate group of animals was        tested at ½ log dose higher until emesis or abnormal behaviour        was observed. The highest dose at which no abnormal behavior or        emetic episodes occurred was recorded as the NOEL.        Materials and Methods        LC-MS Method A

LC-parameters: solution A: acetonitrile solution B: 0.3 g 30% HCl/Lwater column oven 50° C.; column Symmetry C18 2.1 × 150 mm gradient:time [min] % A % B flow [mL/min] 0 10 90 0.9 3 90 10 1.2 6 90 10 1.2LC-MS Method B

LC-parameters: solution A: acetonitrile/0.1% formic acid solution B:water/0.1% formic acid column oven 40° C.; column Symmetry C18 2.1 × 50mm gradient: time [min] % A % B flow [mL/min] 0 10 90 0.5 4 90 10 0.5 690 10 0.5 6.1 10 90 1.0 7.5 10 90 0.5GC-MS Method A

Column: HP-5 30 m × 320 μm × 0.25 μm Carrier Gas: Helium Mode: Constantflow, initial flow: 1.5 mL/min Oven ramp: initial temp: 60° C. initialtime: 1 min rate: 14° C./min up to 300° C., then 300° C. 2 min

Unless specified otherwise, the following chromatographic conditionswere applied: chromatography was performed on silica gel Si 60; forflash chromatography, the usual conditions were followed as described inStill, J. Org. Chem. 43, 2923 (1978); mixtures of dichloromethane andmethanol or cyclohexane and ethylacetate were used as eluants. Unlessspecified otherwise, reactions were executed under an argon atmosphereand under anhydrous conditions.

Abbreviations

-   HPLC=high performance liquid chromatography-   MS=mass spectroscopy-   NMR=nuclear magnetic resonance spectroscopy-   LC-MS=liquid chromatography combined with mass spectroscopy-   GC-MS=gas chromatography combined with mass spectroscopy-   MeOH=methanol-   DMF=dimethylformamide-   DMSO=dinethylsulfoxide-   THF=tetrahydrofuran

STARTING MATERIALS Example 1A 2-(Acetylamino)butanoic acid

163 g (1.58 mol) 2-aminobutanoic acid are dissolved in acetic acid, and242 g (2.37 mol) acetic anhydride are added dropwise. The mixture isstirred for 2 h at 100° C. until completion of reaction, then thesolution is evaporated to dryness in vacuo. The solid residue issuspended in ethyl acetate, filtered and washed with diethyl ether.

Yield: 220 g (95.9%)

¹H-NMR (Methanol-d₄): δ=0.97 (t, 3H), 1.65–1.93 (m, 2H), 1.99 (s, 3H),4.29 (q, 1H) ppm.

Example 2A Ethyl 3-(acetylamino)-2-oxopentanoate

9.2 g (63.4 mmol) 2-(acetylamino)butanoic acid are suspended in 120 mltetrahydrofuran and heated to reflux together with 15.0 g (190 mmol)pyridine and a bit of N,N-dimethylaminopyridine. While heating atreflux, 17.3 g (127 mmol) ethyl chloro(oxo)acetate are added dropwise.The reaction mixture is heated at reflux until no more evolution of gascan be observed. After cooling down to room temperature, the reactionmixture is added to ice water and the organic phase extracted with ethylacetate. The dried organic phase is evaporated to dryness in vacuo,dissolved in ethanol and the solution directly used for the nextreaction.

Example 3A 2-[(Cyclopentylcarbonyl)amino]butanoic acid

35 g (339 mmol) 2-aminobutanoic acid and 75.6 g (747 mmol) triethylamineare suspended in 300 ml of dichloromethane and stirred at 0° C. 81 g(747 mmol) chlorotrimethylsilane are added dropwise, then the mixture isstirred for 1 hour at room temperature and for 1 hour at 40° C. Aftercooling down to −10° C., 45 g (339 mmol) cyclopentanecarbonyl chlorideare added slowly. The reaction mixture is stirred for 2 hours at −10° C.and then for 1 hour at room temperature. At 0° C., 50 ml of water areadded. The mixture is diluted with water and dichloromethane, filteredand the solid product washed with water/dichloromethane 9:1, toluene anddiethylether.

Yield 52.4 g (77%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m, 10H), 2.6 (m, 1H), 4.1(m, 2H), 7.9 (d, 1H), 12.4 (s, 1H) ppm.

Example 4A Ethyl 3-[(cyclopentylcarbonyl)amino]-2-oxopentanoate

1.6 g (8 mmol) 2-[(cyclopentylcarbonyl)amino]butanoic acid are suspendedin 30 ml tetrahydrofuran and heated to reflux together with 1.91 g (24mmol) pyridine and a bit of N,N-dimethylaminopyridine. While heating atreflux, 2.19 g (16 mmol) ethyl chloro(oxo)acetate are added dropwise.The reaction mixture is heated at reflux until no more evolution of gascan be observed. After cooling down to room temperature, the reactionmixture is added to ice water and the organic phase extracted with ethylacetate. The dried organic phase is evaporated to dryness in vacuo,dissolved in ethanol and the solution directly used for the nextreaction.

Example 5A 4-Cyanobenzenecarboximidamide hydrochloride

6.64 g (124 mmol, 2 equiv.) ammonium chloride are suspended in 100 ml ofdry toluene under an argon atmosphere, and the mixture is cooled to 0°C. 62 ml (124 mmol, 2 equiv.) of a 2M solution of trimethylaluminium inhexane are added dropwise, and the reaction mixture is stirred at roomtemperature until no more evolution of gas is observed. After additionof 10.0 g (62 mmol, 1 equiv.) methyl 4-cyanobenzoate, the mixture isstirred at 80° C. bath temperature over night. It is then cooled down to0° C., and 50 ml of methanol are added with consequent stirring for 1hour at room temperature. After filtration, the solid is washed withmethanol for several times, the solution is evaporated to dryness invacuo and the residue washed with methanol.

Yield: 8.5 g (76%)

LC/MS (13): MS (ESI): 145 (M+H)⁺, retention time 0.33 min.

Example 6A 3-Nitrobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 5A, 30.0 g (203 mmol)3-nitrobenzonitrile and proportionate amounts of the other reagents areused.

Yield: 24.5 g (47%)

LC/MS (A): retention time 0.40 min., m/z 166 [M+H]⁺

Example 7A Ethyl4-{6-[1-(acetylamino)propyl]-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl}benzoate

1.98 g (8.66 mmol) ethyl 4-[amino(imino)methyl]benzoate hydrochlorideare suspended in 50 ml of ethanol and 1.47 g (10.2 mmol, 1.2 equiv.)hydrazine hydrate are added. After stirring at room temperature for 1hour, 2.59 g (13 mmol, 1.5 equiv.) of the compound of Example 2A,dissolved in 10 ml of ethanol, are added. The reaction mixture isstirred at 80° C. (bath temperature) for 4 hours and then at roomtemperature over night. The mixture is evaporated to dryness in vacuoand the product is purified by chromatography (flash or columnchromatography or preparative HPLC).

Yield: 1.42 g (48%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.4 (t, 3H), 1.6 (m, 1H), 1.8(m, 1H), 1.9 (s, 3H), 4.4 (q, 2H), 4.9 (m, 1H), 8.2 (m, 4H), 14.2 (br.s, 1H) ppm.

Example 8AN-{1-[3-(4-Hydroxyphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 7A, 5.0 g (29.0 mmol)4-hydroxybenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 4.23 g (51%)

LC/MS (B): MS (ESI): 289 (M+H)⁺, retention time 1.65 min.

Example 9AN-{1-[3-(4-Cyanophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 7A, 8.4 g (46.3 mmol) of Example5A and proportionate amounts of the other reagents are used.

Yield: 5.77 g (42%)

LC/MS (A): MS (ESI): 298 (M+H)⁺, retention time 1.64 min.

Example 10AN-{1-[3-(3-Nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 7A, 35.0 g (174 mmol)3-nitrobenzenecarboximidamide hydrochloride and proportionate amounts ofthe other reagents are used.

Yield: 13.6 g (25%)

¹H-NMR (200 MHz, CDCl₃): δ=0.97 (t, 3H), 1.83–2.08 (m, 5H, s at 2.02),5.09 (m, 1H), 7.33 (d, 1H, NH), 7.76 (t, 1H), 8.45 (d, 1H), 8.58 (d,1H), 9.12 (s, 1H) ppm.

Example 11A4-(6-{1-[(Cyclopentylcarbonyl)amino]propyl}-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)-benzamide

2.84 g (14.2 mmol, 1 equiv.) 4-[amino(imino)methyl]benzamidehydrochloride are suspended in 10 ml of ethanol and 1.37 g (26.8 mmol,1.2 equiv.) hydrazine hydrate are added. After stirring at 60° C. for 1hour, 6.28 g (24.6 mmol, 1.1 equiv.) ethyl3-[(cyclopentylcarbonyl)-amino]-2-oxopentanoate (Example 4A), dissolvedin 40 ml of ethanol, are added. The reaction mixture is stirred at 70°C. (bath temperature) for 4 hours. The mixture is evaporated to drynessin vacuo and the product is purified by flash chromatography.

Yield: 45 mg (1%)

LC/MS (A): MS (ESI): 369 (M+H)⁺, retention time 2.66 min.

Example 12A4-[6-(1-Aminopropyl)-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl]benzoic acid

1.36 g (3.95 mmol) of Example 7A are heated to reflux in 20 ml 2 Nhydrochloric acid for 18 hours. After cooling down to room temperature,the mixture is neutralized with 10% sodium hydroxide and, after additionof ethanol, evaporated to dryness in vacuo. The residue is treated withmethanol and the filtrate separated from the salts. The filtrate isevaporated to dryness in vacuo and the product purified bychromatography (flash or column chromatography or preparative HPLC).

Yield: 1.12 g (quant.)

LC/MS (A): MS (ESI): 275 (M+H)⁺, retention time 0.45 min.

Example 13A6-(1-Aminopropyl)-3-(4-hydroxyphenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 12A, 4.22 g (14.6 mmol) ofExample 8A and proportionate amounts of the other reagents are used. Theproduct is used in the next step without further purification.

LC/MS (3): MS (ESI): 247 (M+H)⁺, retention time 0.35 min.

Example 14A4-[6-(1-Aminopropyl)-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl]benzonitrile

In analogy to the procedure for Example 12A, 5.70 g (19.2 mmol) ofExample 9A and proportionate amounts of the other reagents are used.

LC/MS (A): MS (ESI): 256 (M+H)⁺, retention time 0.49 min.

Example 15A 6-(1-Aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 12A, 13.5 g (42.5 mmol)N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide(example 10A) and proportionate amounts of the other reagents are used.

Yield: 6.2 g (41%)

LC/MS (A): retention time 0.497 min., m/z 276 [M+H]⁺

Example 16A4-(6-{1-[(Cyclobutylcarbonyl)amino]propyl}-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzoicacid

584 mg (2.13 mmol) of Example 12A are suspended in 10 mldichloromethane, 431 mg (4.26 mmol, 2 equiv.) triethylamine and 252 mg(2.13 mmol, 1 equiv.) cyclobutanecarbonyl chloride are added. Thereaction mixture is stirred at room temperature until completion ofreaction (1–2 hours). The reaction mixture is added to the same volumeof 1N hydrochloric acid, the organic phase is washed with 1Nhydrochloric acid and brine, dried over sodium sulfate and evaporated todryness. The product is used without further purification or purified bychromatography (flash or column chromatography or preparative HPLC).

Yield: 106 mg (14%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m, 1H), 1.8 (m, 3H), 2.0(m, 2H), 2.1 (m, 2H), 3.1 (m, 1H), 4.9 (m, 1H), 7.9 (d, 1H), 8.1 (m,4H), 13.5 (br, 1H), 14.2 (br, 1H) ppm.

Example 17A4-(6-{1-[(Cyclopentylcarbonyl)amino]propyl}-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl)benzoicacid

In analogy to the procedure for Example 16A, 550 mg (2.01 mmol) ofExample 12A, 266 mg (2.01 mmol) cyclopentanecarbonyl chloride andproportionate amounts of the other reagents are used.

Yield: 211 mg (28%)

LC/MS (B): MS (ESI): 371 (M+)⁺, retention time 2.93 min.

Example 18AN-{1-[3-(4-Hydroxyphenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclo-pentanecarboxamide

In analogy to the procedure for Example 16A, 200 mg (0.81 mmol) ofExample 13A, 102 mg (0.89 mmol) cyclopentanecarbonyl chloride andproportionate amounts of the other reagents are used.

Yield: 24 mg (28%)

LC/MS (A): MS (ESI): 343 (M+H)⁺, retention time 2.00 min.

Example 19AN-{1-[3-(3-Nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclopentane-carboxamide

In analogy to the procedure for Example 16A, 3.0 g (10.9 mmol)6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one (Example15A), 2.2 g (16.3 mmol) cyclopentanecarbonyl chloride and proportionateamounts of the other reagents are used.

Yield: 3.9 g (93%)

¹H-NMR (200 MHz, CDCl₃): δ=0.91 (t, 3H), 1.54–2.09 (m, 10H), 2.71(quint, 1H), 5.25 (m, 1H), 7.59 (m, NH), 7.74 (t, 1H), 8.48 (d, 1H),8.64 (d, 1H), 9.25 (s, 1H) ppm.

Example 20Acis-4-tert-Butyl-N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]-propyl}cyclohexanecarboxamide

In analogy to the procedure for Example 16A, 3.2 g (11.6 mmol)6-(1-aminopropyl)-3-(3-nitrophenyl)-1,2,4-triazin-5(4H)-one (Example15A), 2.4 g (11.6 mmol) cis-4-tert.-butylcyclohexanecarbonyl chloride(Example 42A) and proportionate amounts of the other reagents are used.The crude product is used in the next step without further purification.

Yield: 5.1 g (crude)

Example 21A7-Cyclopentyl-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

3.5 g (9.4 mmol)N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-cyclopentanecarboxamide(Example 19A) are suspended in 60 ml dichloroethane, and 1.45 g (9.4mmol) phosphoroxychloride are added. The mixture is stirred at refluxfor 3 hour. After cooling down to 0° C., 10 ml saturated NaHCO₃ (aq) isadded dropwise. The mixture is stirred for about 20 min at roomtemperature and then evaporated to dryness in vacuo. The product ispurified by chromatography (flash or column chromatography).

Yield: 1.8 g (54%)

¹H-NMR (200 MHz, CDCl₃): δ=1.33 (t, 3H), 1.63–2.22 (m, 8H), 3.03 (q,2H), 3.68 (quin., 1H), 7.76 (t, 1H), 8.38–8.48 (m, 2H), 8.89–8.95 (s,1H), 10.85 (s, 1H, NH) ppm.

Example 22A7-(4-tert-Butylcyclohexyl)-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 21A, 5.1 g (11.6 mmol) crudecis-4-tert-butyl-N-{1-[3-(3-nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}cyclo-hexanecarboxamide(Example 20A), 2.7 g (17.4 mmol) phosphoric trichloride are stirred atreflux for 3 hours and proportionate amounts of the solvents are used.

Yield: 3.0 g (61%)

Example 23Acis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzonitrile

900 mg (3.53 mmol) of Example 14A are suspended in 50 ml dichloroethane,and 535 mg (5.3 mmol) triethylamine and 715 mg (3.53 mmol)cis-4-tert-butylcyclohexyl-carbonyl chloride (Example 42A) are added.The mixture is stirred at room temperature for one hour, then 811 mg(5.29 mmol) phosphoroxychloride are added. The mixture is stirred atreflux for 3 hours. After cooling down to room temperature, ethylacetate and saturated NaHCO₃ (aq) are added. The organic phase is washedwith saturated NaHCO₃ (aq), water and brine, dried over sodium sulfateand evaporated to dryness in vacuo. The product is purified bychromatography (flash or column chromatography or preparative HPLC).

Yield: 529 mg (37%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (t, 2H), 3.6 (m, 1H), 8.0 (m, 1H), 8.1(m, 1H), 12.0 (s, 1H) ppm.

Example 24AN-{1-[3-(3-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

2.02 g (8.6 mmol, 1 equiv.) 3-bromobenzenecarboximidamide hydrochloride(Example 31A) are suspended in 50 ml of ethanol, and 1.47 g (10.2 mmol,1.2 equiv.) hydrazine hydrate are added. After stirring at roomtemperature for 1 hour, 2.59 g (13 mmol, 1.5 equiv.) of the compound ofExample 2A, dissolved in 10 l of ethanol, are added. The reactionmixture is stirred at 80° C. (bath temperature) for 4 hours and then atroom temperature over night. The mixture is evaporated to dryness invacuo and the product is purified by chromatography (flash or columnchromatography or preparative HPLC).

Yield: 758 mg (25%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.6 (m, 1H), 1.8 (m, 1H), 1.9(s, 3H), 4.9 (m, 1H), 7.5 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.2 (m,2H), 14.1 (br. s, 1H) ppm.

Example 25A 6-(1-Aminopropyl)-3-(3-bromophenyl)-1,2,4-triazin-5(4H)-one

749 mg (2.13 mmol) of Example 24A are heated to reflux in 20 ml 2 Nhydrochloric acid for 18 hours. After cooling down to room temperature,the mixture is neutralized with 10% sodium hydroxide and, after additionof ethanol, evaporated to dryness in vacuo. The residue is treated withmethanol and the filtrate separated from the salts. The filtrate isevaporated to dryness in vacuo and the product purified bychromatography (flash or column chromatography or preparative HPLC).

Yield: 320 mg (49%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.9 (m, 2H), 4.3 (dd, 1H), 7.4(m, 1H), 7.6 (m, 1H), 8.1 (br. s, 2H), 8.2 (m, 1H), 8.4 (m, 1H) ppm.

Example 26AN-{1-[3-(3-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}-4-tert-butyl-cyclohexanecarboxamide

500 mg (1.62 mmol, 1 equiv.) of Example 25A are suspended in 40 mldichloromethane, 0.48 ml (3.44 mmol, 2 equiv.) triethylamine and 328 mg(1.62 mmol) 4-tert-butylcyclohexanecarbonyl chloride are added. Thereaction mixture is stirred at room temperature until completion ofreaction (1–2 hours). The reaction mixture is added to the same volumeof 1N hydrochloric acid, the organic phase is washed with 1Nhydrochloric acid and brine, dried over sodium sulfate and evaporated todryness. The product is used without further purification or purified bychromatography (flash or column chromatography or preparative HPLC).

LC/MS (A): MS (ESI): 475, 477 (M+H)⁺, retention time 3.17, 3.20 min.

Example 27A2-(3-Bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

770 mg (1.62 mmol, 1 equiv.) of Example 26A are suspended in 70 mldichloroethane, and 373 mg (2.45 mmol, 1.5 equiv.) phosphoroxychlorideare added. The mixture is stirred at reflux for 3 hours. Then another373 mg of phosphoric trichloride are added, and stirring at reflux iscontinued over night. After cooling down to room temperature, ethylacetate and saturated NaHCO₃ (aq) are added. The organic phase is washedwith saturated NaHCO₃ (aq), water and brine, dried over sodium sulfateand evaporated to dryness in vacuo. The product is purified and theisomers are separated by chromatography (flash or column chromatographyor preparative HPLC).

Yield: 156 mg (21%) cis-isomer

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 2H), 1.2 (t, 3H), 1.5(m, 2H), 1.7 (m, 2H), 2.2 (m, 2H), 2.9 (q, 2H), 3.5 (m, 1H), 7.5 (m,1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.1 (m, 1H), 11.8 (s, 1H) ppm.

Example 28AN-{1-[3-(4-Bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 24A, 10.2 g (43.3 mmol)4-bromobenzene-carboximidamide hydrochloride and proportionate amountsof the other reagents are used.

Yield: 5.23 g (34%)

¹H-NMR (400 MHz, CD₃OD): δ=1.01 (t, 3H), 1.66–1.79 (m, 1H), 1.91–2.06(m, 4H, s at 1.99), 5.02–5.09 (m, 1H), 7.75 (d, 2H), 7.93 (d, 2H) ppm.

Example 29A 6-(1-Aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 25A, 5.0 g (14.2 mmol)N-{1-[3-(4-bromophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide(Example 28A) and proportionate amounts of the other reagents are used.

Yield: 3.4 g (77%)

¹H-NMR (300 MHz, CD₃OD): δ=1.02 (t, 3H), 1.87–2.22 (m, 5H, s at 1.96),4.42–4.53 (t, 1H), 7.63 (d, 2H), 8.09 (d, 2H) ppm.

Example 30Acis-2-(4-Bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one

In analogy to the procedure for Example 23A, 7.6 g (24.6 mmol)6-(1-aminopropyl)-3-(4-bromophenyl)-1,2,4-triazin-5(4H)-one (Example29A), 4.98 g (24.55 mmol) cis-4-tert-butylcyclohexylcarbonyl chloride(Example 42A) and proportionate amounts of the other reagents are used.

Yield: 7.89 g (70%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 3H), 7.7 (m, 2H), 7.9(m, 2H) ppm.

Example 31A 3-Bromobenzenecarboximidamide hydrochloride

1.18 g (22 mmol, 2 equiv.) ammonium chloride are suspended in 40 ml ofdry toluene under an argon atmosphere, and the mixture is cooled to 0°C. 11 ml (22 mmol, 2 equiv.) of a 2M solution of trimethylaluminium inhexane are added dropwise, and the reaction mixture is stirred at roomtemperature until no more evolution of gas is observed. After additionof 2.0 g (11 mmol, 1 equiv.) 3-bromobenzonitrile, the mixture is stirredat 80° C. bath temperature over night. It is then cooled down to 0° C.,and 50 ml of methanol are added with subsequent stirring for 1 hour atroom temperature. After filtration, the solid is washed with methanolfor several times, the solution is evaporated to dryness in vacuo andthe residue washed with methanol.

Yield: 2.02 g (78%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=7.6 (m, 1H), 7.8 (m, 1H), 8.0 (m, 1H), 8.1(s, 1H) ppm.

Example 32A 4-Nitrobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 31A, 10.0 g (67.5 mmol)4-nitrobenzonitrile and proportionate amounts of the other reagents areused.

Yield: 12.64 g (93%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=8.1 (m, 2H), 8.4 (m, 2H) ppm.

Example 33AN-{1-[3-(4-Nitrophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 24A, 7.29 g (36.16 mmol) ofExample 32A and proportionate amounts of the other reagents are used.

Yield: 3.35 g (29%)

¹H-NMR (DMSO-d₆, 400 MHz): δ=0.9 (t, 3H), 1.6 (m, 1H), 1.9 (m, 1H; s,3H), 5.0 (m, 1H), 8.1 (d, 1H), 8.3 (m, 2H), 8.4 (m, 2H) ppm.

Example 34A 6-(1-Aminopropyl)-3-(4-nitrophenyl)-1,2,4-triazin-5(4H)-one

In analogy to the procedure for Example 25A, 3.33 g (10.51 mmol) ofExample 33A and proportionate amounts of the other reagents are used.

Yield: 1.29 g (45%)

LC/MS (A): MS (ESI): 276 (M+H)⁺, retention time 0.49 min.

Example 35Acis-7-(4-tert-Butylcyclohexyl)-4-chloro-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f]-[1,2,4]triazine

500 mg (1.82 mmol) of Example 34A are suspended in 20 ml dichloroethane,and 276 mg (2.72 mmol) triethylamine and 552 mg (2.72 mmol)cis-4-tert-butylcyclohexanecarbonyl chloride (Example 42A) are added.The mixture is stirred at room temperature for one hour, then 279 mg(1.82 mmol) phosphoroxychloride are added. The mixture is stirred atreflux for 3 hours. After cooling down to room temperature, ethylacetate and saturated NaHCO₃ (aq) are added. The organic phase is washedwith saturated NaHCO₃ (aq), water and brine, dried over sodium sulfateand evaporated to dryness in vacuo. The product is purified bychromatography.

Yield: 127 mg (16%) cis-product

MS (ESI): 442, 444 (M+H⁺).

Example 36A7-(cis-4-tert-Butylcyclohexyl)-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

598 mg (1.35 mmol) of Example 35A are suspended in methanol, and 10 mlsodium hydroxide (10% in water) are added. The mixture is stirred atreflux over night. After cooling down to room temperature, the methanolis evaporated in vacuo, the residue dissolved in ethyl acetate, theorganic phase washed with water and brine, dried over sodium sulfate andevaporated to dryness in vacuo.

Yield: 580 mg (quant.)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 8.2 (m, 2H), 8.4(m, 2H), 12.1 (s, 1H) ppm.

Example 37A 3-Cyanobenzenecarboximidamide hydrochloride

In analogy to the procedure for Example 31A, 20.0 g (125.9 mmol)3-cyanobenzoic acid and proportionate amounts of the other reagents areused.

Yield: 4.27 g (17%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=7.8 (m, 1H), 8.1 (m, 1H), 8.2 (m, 1H), 8.3(m, 1H), 9.4 (br. s, 4H) ppm.

Example 38AN-{1-[3-(3-Cyanophenyl)-5-oxo-4,5-dihydro-1,2,4-triazin-6-yl]propyl}acetamide

In analogy to the procedure for Example 24A, 4.27 g (23.5 mmol) ofExample 37A and proportionate amounts of the other reagents are used.

Yield: 2.41 g (34%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.9 (t, 3H), 1.6 (m, 1H), 1.9 (m, 1H; s,3H), 4.9 (m, 1H), 7.8 (m, 1H), 8.1 (m, 2H), 8.3 (m, 1H), 8.4 (m, 1H),14.2 (br. s, 1H) ppm.

Example 39A3-[6-(1-Aminopropyl)-5-oxo-4,5-dihydro-1,2,4-triazin-3-yl]benzonitrile

In analogy to the procedure for Example 25A, 2.41 g (8.11 mmol) ofExample 38A and proportionate amounts of the other reagents are used.

Yield: 1.1 g (53%)

LC/MS (A): MS (ESI): 256 (M+H)⁺, retention time 1.27 min.

Example 40Acis-3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzonitrile

In analogy to the procedure for Example 23A, 1.09 g (4.27 mmol) ofExample 39A, 0.86 g (4.27 mmol) cis-4-tert-butylcyclohexanecarbonylchloride (Example 42A) and proportionate amounts of the other reagentsare used.

Yield: 0.70 g (41%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 7.7 (m, 1H), 8.0(m, 1H), 8.3 (m, 1H), 8.4 (m, 1H), 11.9 (s, 1H) ppm.

Example 41A cis- and trans-4-tert-Butylcyclohexanecarboxylic acid

A preparative HPLC separation of cis- andtrans-4-tert-butylcyclohexanecarboxylic acid was carried out under thefollowing conditions:

Feed: 10 g isomeric mixture of cis- and trans-4-tert-butyl-cyclo-hexanecarboxylic acid dissolved in 500 ml iso-hexane(80%)/tert-butylmethylether (20%) Column: 330 × 100 mm; Self PackingDevice NW 100; Merck Stationary phase: LiChrospher Si 60, 12 μm, MerckMobile phase: iso-hexane/tert-butylmethylether (4/1 v/v) + 0.25 vol-%acetic acid Flow: 150 ml/min Injection volume: 70 ml (=1.4 g compound)Wave length: 210 nm Temperature: 25° C.

The sample run on this column was repeatedly injected every 30 minutes.The cis-isomer is the first eluting compound.

cis-isomer:

mp.: 118° C.

¹H-NMR (300 MHz, DMSO): δ=0.9 (t, 3H), 1.0 (m, 3H), 1.4 (m, 2H), 1.6 (m,1H), 2.1 (m, 2H), 2.5 (m, 1H), 12.0 (s, 1H) ppm.

trans-isomer:

mp.: 172° C.

¹H-NMR (300 MHz, DMSO): δ=0.9 (t, 3H), 1.0 (m, 3H), 1.3 (m, 2H), 1.7 (m,1H), 1.9 (m, 2H), 2.1 (m, 1H), 11.9 (s, 1H) ppm.

Example 42A cis-4-tert-Butylcyclohexanecarbonyl chloride

2.0 g (10.85 mmol) cis-4-tert-Butylcyclohexanecarboxylic acid aredissolved in 50 ml dichloromethane, 1.65 g (13.02 mmol) ethanedioyldichloride are added and the solution is stirred at room temperature forone hour. The mixture is then stirred at reflux for two hours and, aftercooling down to room temperature, evaporated to dryness in vacuo. Theresidue is then dissolved in toluene two times and again evaporated todryness in vacuo. The residue is used in the next step without furtherpurification.

Example 43A trans-4-tert-Butylcyclohexanecarbonyl chloride

11.0 g (59.7 mmol) trans-4-tert-Butylcyclohexanecarboxylic acid aredissolved in 400 ml dichloromethane plus a few drops of DMF, 9.09 g(71.6 mmol) ethanedioyl dichloride are added and the solution is stirredat room temperature for one hour. The mixture is then stirred at refluxfor two hours and, after cooling down to room temperature, evaporated todryness in vacuo. The residue is then dissolved in toluene two times andagain evaporated to dryness in vacuo. The residue is used in the nextstep without further purification.

PREPARATION EXAMPLES Example 14-(7-Cyclobutyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzoicacid

175 mg (0.49 mmol, 1 equiv.) of Example 16A are suspended in 10 mldichloroethane, and 113 mg (0.74 mmol, 1.5 equiv.) phosphoroxychlorideare added. The mixture is stirred at reflux for 3 hours. After coolingdown to room temperature, ethyl acetate and saturated NaHCO₃ (aq) areadded. The organic phase is washed with saturated NaHCO₃ (aq), water andbrine, dried over sodium sulfate and evaporated to dryness in vacuo. Theproduct is purified by chromatography (flash or column chromatography orpreparative HPLC).

Yield: 42 mg (25%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.9 (m, 1H), 2.1 (m, 2H), 2.3(m, 2H), 2.4 (m, 1H), 2.9 (q, 2H), 4.0 (m, 1H), 7.9 (m, 4H) ppm.

Example 24-(7-Cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzoicacid

In analogy to the procedure for Example 1, 205 mg (0.55 mmol) of Example17A, 127 mg (0.83 mmol) phosphoric trichloride are stirred at reflux for3 hours and proportionate amounts of the solvents are used.

Yield: 135 mg (69%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.6–1.9 (m, 6H), 2.1 (m, 2H),3.0 (q, 2H), 3.7 (m, 1H), 8.1 (m, 4H), 12.3 (s, 1H) ppm.

Example 34-(7-Cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-propylbenzamide

40 mg (0.11 mmol) of Example 2 are dissolved in dimethylformamide, 7.4mg (0.12 mmol) n-propylamine, 17 mg (0.11 mmol)1-hydroxy-1H-benzotriazole hydrate and 14 mg (0.11 mmol)4-dimethylaminopyridine are added. The reaction mixture is stirred at 0°C., then 24 mg (0.12 mmol) 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride are added. The mixture is stirred at room temperature for18 hours, water is added and the resulting solid product is filtered.

Yield: 27 mg (61%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.2 (t, 3H), 1.6 (m, 2H),1.7–1.9 (m, 6H), 2.1 (m, 2H), 2.9 (q, 2H), 3.2 (m, 2H), 3.6 (m, 1H), 8.0(m, 4H), 8.6 (br. t, 1H), 11.9 (s, 1H) ppm.

Example 44-(7-Cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)-N-phenylbenzamide

In analogy to the procedure for Example 3, 40 mg (0.11 mmol) of Example2, 12 mg (0.12 mmol) aniline and proportionate amounts of the otherreagents are used.

Yield: 20 mg (42%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.7–1.9 (m, 6H), 2.1 (m, 2H),2.9 (q, 2H), 3.6 (m, 1H), 7.1 (m, 1H), 7.4 (m, 2H), 7.8 (m, 2H), 8.1 (m,4H), 10.4 (s, 1H), 12.0 (s, 1H) ppm.

Example 57-Cyclopentyl-5-ethyl-2-(4-hydroxyphenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 1, 20 mg (0.06 mmol) of Example18A, 13 mg (0.09 mmol) phosphoric trichloride are stirred at reflux for3 hours and proportionate amounts of the solvents are used.

Yield: 9 mg (48%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.9 (t, 3H), 1.6 (m, 2H), 1.8 (m, 4H), 2.1(m, 2H), 3.0 (q, 2H), 3.6 (m, 1H), 6.9 (m, 2H), 7.9 (m, 2H), 10.1 (s,1H), 11.6 (s, 1H) ppm.

Example 6cis-2-(4-Aminophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

580 mg (1.37 mmol)cis-7-(4-tert-butylcyclohexyl)-5-ethyl-2-(4-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 36A) are dissolved in 50 ml tetrahydrofuran and catalyticamounts of palladium (10% on charcoal) are added. The mixture is stirredfor 18 hour at room temperature in a 3 bar hydrogen atmosphere. Then themixture is filtrated and the organic phase evaporated to dryness invacuo.

Yield: 433 mg (80%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.4 (q, 2H), 3.5 (m, 1H), 5.7 (s, 2H), 6.6(m, 2H), 7.7 (m, 2H), 11.4 (s, 1H) ppm.

Example 7cis-N-{4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}acetamide

In analogy to the procedure for Example 3, 50 mg (0.13 mmol) of Example6, 8 mg (0.14 mmol) acetic acid and proportionate amounts of the otherreagents are used.

Yield: 7 mg (12%)

LC/MS (A): MS (ESI): 436 (M+H)⁺, retention time 2.75 min.

Example 8cis-7-(4-tert-Butylcyclohexyl)-2-{4-[(cyclohexylmethyl)amino]phenyl}-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

35 mg (0.09 mmol) of Example 6 are dissolved in 5 ml methanol, 20 mg(0.18 mmol) cyclohexanecarbaldehyde and 6 mg (0.09 mmol) sodiumcyanoborohydride are added. The reaction mixture is stirred at roomtemperature for 2 hours and quenched with 2 N hydrochloric acid. Themethanol is evaporated in vacuo and dichloromethane is added to theaqueous residue. The organic phase is dried over sodium sulfate,evaporated to dryness in vacuo, triturated with diethyl ether and thesolid product is isolated.

Yield: 30 mg (69%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.0 (m, 1H), 1.2 (m, 4H), 1.2(t, 3H), 1.4 (m, 2H), 1.6–1.8 (m, 10H), 2.3 (m, 2H), 2.9 (m, 4H), 6.6(m, 2H), 7.8 (m, 2H), 11.7 (s, 1H) ppm.

Example 9 cis-Ethyl(2E)-3-{3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl]phenyl}-2-propenoate

740 mg (1.62 mmol)cis-2-(3-bromophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 27A), 1.6 g (16.2 mmol) ethyl acrylate, 327 mg (3.24 mmol)triethylamine and 227 mg (0.32 mmol)dichlorobis(triphenylphosphine)palladium(II) are stirred at 120° C. in20 ml DMF in an argon atmosphere for 18 hours. After cooling down toroom temperature, the mixture is filtrated over Celite, and the productis isolated by column chromatography or preparative HPLC.

Yield: 447 mg (58%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.3(t, 3H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 4.2 (q,2H), 6.8 (d, 1H), 7.6 (m, 1H), 7.7 (d, 1H), 7.9 (m, 1H), 8.0 (m, 1H),8.4 (m, 1H), 11.8 (s, 1H) ppm.

Example 10cis-(2E)-3-{3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}-2-propenoicacid

200 mg (0.42 mmol) of Example 9 are dissolved in 5 ml ethanol, 5 mlsodium hydroxide (10% in water) are added and the mixture is stirred atroom temperature for 18 hours. Hydrochloric acid is added (pH<7),followed by dichloromethane. The phases are separated, the organic phaseis dried over sodium sulfate and evaporated to dryness in vacuo. Theproduct is purified by column chromatography or preparative HPLC.

Yield: 177 mg (94%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 6.7 (d, 1H), 7.6(m, 2H), 7.8 (m, 1H), 8.0 (m, 1H), 8.3 (m, 1H) ppm.

Example 11cis-(2E)-3-{3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}-N-propyl-2-propenamide

In analogy to the procedure for Example 3, 70 mg (0.16 mmol) of Example10, 18 mg (0.31 mmol) n-propylamine and proportionate amounts of theother reagents are used.

Yield: 59 mg (70%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 0.9 (t, 3H), 1.1 (m, 1H), 1.2(t, 3H), 1.5 (m, 2H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.2 (q,2H), 3.7 (d, 1H), 6.7 (d, 1H), 7.5 (d, 1H), 7.6 (m, 1H), 7.9 (m, 1H),8.2 (m, 1H), 8.3 (m, 1H), 11.9 (m, 1H) ppm.

Example 12cis-(2E)-3-{3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}-N,N-diethyl-2-propenamide

In analogy to the procedure for Example 3, 65 mg (0.14 mmol) of Example10, 21 mg (0.29 mmol) diethylamine and proportionate amounts of theother reagents are used.

Yield: 31 mg (43%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (br. t, 3H; m, 1H), 1.2(br. t, 3H; t, 3H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.4 (m,2H), 3.6 (m, 3H), 7.2 (d, 1H), 7.5 (d, 1H), 7.6 (m, 1H), 7.9 (m, 2H),8.2 (m, 1H), 11.8 (s, 1H) ppm.

Example 13 cis-Ethyl3-{3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}propanoate

In analogy to the procedure for Example 6, 178 mg (0.37 mmol) of Example9 are dissolved in 10 ml methanol and hydrogenated. The product ispurified by column chromatography.

Yield: 147 mg (82%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.3(t, 3H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.7 (t, 2H), 2.9 (m, 4H), 3.6 (m,1H), 4.1 (q, 2H), 7.4 (m, 2H), 7.7 (m, 1H), 7.8 (m, 1H), 11.7 (s, 1H)ppm.

Example 14cis-3-{3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]phenyl}propanoicacid

In analogy to the procedure for Example 10, 170 mg (0.36 mmol) ofExample 13 are used.

Yield: 70 mg (44%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.6 (t, 2H), 2.9 (m, 4H), 3.6 (m, 1H), 7.4(m, 2H), 7.8 (m, 1H), 7.9 (m, 1H) ppm.

Example 15cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzoicacid

500 mg (1.24 mmol) of Example 23A are dissolved in 25 ml ethanol and 25ml concentrated hydrochloric acid. The mixture is stirred at 110° C. for18 hours. After cooling down to room temperature, an aqueous solution ofsodium hydroxide is added to achieve a pH of 6–7. Ethyl acetate is thenadded, the organic phase dried over sodium sulfate and evaporated todryness in vacuo. The product is purified by chromatography (flash orcolumn chromatography or preparative HPLC).

Yield: 327 mg

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (t, 2H), 3.6 (m, 1H), 8.0 (m, 4H) ppm.

Example 16cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzamide

Using the procedure for the preparation of Example 15, Example 16 wasobtained as a by-product.

Yield: 75 mg (16%)

LC/MS (A): MS (ESI): 422 (M+H)⁺, retention time 2.69 min.

Example 17cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]-N-propylbenzamide

In analogy to the procedure for Example 3, 35 mg (0.08 mmol) of Example15, 5 mg (0.09 mmol) n-propylamine and proportionate amounts of theother reagents are used.

Yield: 27 mg (71%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 0.9 (t, 3H), 1.1 (m, 1H), 1.2(t, 3H), 1.5–1.7 (m, 8H), 2.2 (m, 1H), 2.9 (q, 2H), 3.3 (m, 2H), 3.6 (m,1H), 8.0 (m, 4H), 8.6 (br. t, 1H), 11.9 (s, 1H) ppm.

Example 18cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]-N,N-diethylbenzamide

In analogy to the procedure for Example 3, 32 mg (0.08 mmol) of Example15, 6 mg (0.08 mmol) diethylamine and proportionate amounts of the otherreagents are used.

Yield: 31 mg (85%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 7H), 1.2 (t, 3H),1.5–1.7 (m, 8H), 2.2 (m, 1H), 2.9 (q, 2H), 3.2 (br. m, 2H), 3.4 (br. m,2H), 3.6 (m, 1H), 7.5 (m, 2H), 8.0 (m, 2H), 11.8 (s, 1H) ppm.

Example 19cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]-N-cyclohexylbenzamide

In analogy to the procedure for Example 3, 32 mg (0.08 mmol) of Example15, 8 mg (0.08 mmol) cyclohexylamine and proportionate amounts of theother reagents are used.

Yield: 31 mg (80%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.3(m, 4H), 1.5–1.8 (m, 10H), 1.9 (m, 2H), 2.2 (m, 2H), 2.9 (q, 21), 3.6(m, 1H), 3.8 (m, 1H), 7.9 (m, 2H), 8.0 (m, 2H), 8.3 (d, 1H), 11.9 (s,1H) ppm.

Example 20cis-4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]-N-cyclohexyl-N-methylbenzamide

In analogy to the procedure for Example 3, 32 mg (0.08 mmol) of Example15, 9 mg (0.08 mmol) N-methylcyclohexylamine and proportionate amountsof the other reagents are used.

Yield: 35 mg (88%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.8 (m, 16H), 2.2 (m, 2H), 2.8 (m, 1H), 2.9 (q, 2H), 3.6 (m, 1H),7.5 (m, 2H), 8.0 (m, 2H) ppm.

Example 21cis-7-(4-tert-Butylcyclohexyl)-5-ethyl-2-[4-(4-morpholinylcarbonyl)phenyl]imidazo-[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 3, 32 mg (0.08 mmol) of Example15, 7 mg (0.08 mmol) morpholine and proportionate amounts of the otherreagents are used.

Yield: 31 mg (82%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.8 (m, 6H), 21.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 9H), 7.5 (m, 2H),8.0 (m, 2H), 11.9 (s, 1H) ppm.

Example 22cis-7-(4-tert-Butylcyclohexyl)-5-ethyl-2-[4-(1-piperidinylcarbonyl)phenyl]imidazo-[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 3, 32 mg (0.08 mmol) of Example15, 7 mg (0.08 mmol) piperidine and proportionate amounts of the otherreagents are used.

Yield: 31 mg (83%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 14H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 3H), 7.5 (m, 2H),8.0 (m, 2H), 11.9 (s, 1H) ppm.

Example 23cis-3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzamide

100 mg (0.25 mmol)cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile(Example 40A) are dissolved in 5 ml ethanol and 10 ml water. 342 mg(2.48 mmol) potassium carbonate and 281 mg (2.48 mmol) hydrogeneperoxide are added. The reaction mixture is stirred at room temperaturefor 18 hours. Dichloromethane is added, the organic phase separated,dried over sodium sulfate and evaporated to dryness in vacuo.

Yield: 97.6 mg (93%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 7.5 (m, 1H), 7.6(m, 1H), 8.1 (m, 3H), 8.4 (m, 1H), 11.8 (s, 1H) ppm.

Example 24cis-3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]benzoicacid

108 mg (0.27 mmol)cis-3-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl]benzonitrile(Example 40A) are dissolved in concentrated hydrochloric acid, and thereaction mixture is stirred at 95° C. for three hours. Sodium hydroxide(10% aqueous solution) (until a pH of 6–7 is achieved) and ethylacetateare added. The organic phase is dried over sodium sulfate and evaporatedto dryness in vacuo. The product is purified by column chromatography.

Yield: 15 mg (13%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 7.5 (m, 1H), 8.0(m, 1H), 8.1 (8m, 1H), 8.5 (m, 1H) ppm.

Example 25 cis-Ethyl(2E)-3-{4-[7-(4-tert-butylcyclohexyl)-5-ethyl-oxo-3,4-dihydroimidazo-[5,1-f][1,2,4]triazin-2-yl]phenyl}-2-propenoate

In analogy to the procedure for Example 9, 3.0 g (6.56 mmol) of Example30A, 6.57 g (65.69 mmol) ethyl acrylate and proportionate amounts of theother reagents are used.

Yield: 1.81 g (58%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.3(t, 3H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 4.2 (q,2H), 6.8 (d, 1H), 7.7 (d, 1H), 7.9 (m, 2H), 8.0 (m, 2H), 11.8 (s, 1H)ppm.

Example 26cis-(2E)-3-{4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}-2-propenoicacid

In analogy to the procedure for Example 10, 882 mg (1.85 mmol) ofExample 25 are used.

Yield: 529 g (64%)

¹H-NMR (DMSO-d₆, 200 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.9 (q, 2H), 3.6 (m, 1H), 6.7 (d, 1H), 7.7(d, 1H), 7.9 (m, 2H), 8.0 (m, 2H), 12.1 (s, 1H) ppm.

Example 27 cis-Ethyl3-{4-[7-(4-tert-butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f]-[1,2,4]triazin-2-yl]phenyl}propanoate

In analogy to the procedure for Example 6, 900 mg (1.89 mmol) of Example25 are dissolved in 10 ml methanol and hydrogenated. The product ispurified by column chromatography.

Yield: 368 mg (41%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H), 1.3(t, 3H), 1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.7 (t, 2H), 2.9 (m, 4H), 3.6 (m,1H), 4.1 (q, 2H), 7.4 (m, 2H), 7.9 (m, 1H), 11.7 (s, 1H) ppm.

Example 28cis-3-{4-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl]phenyl}propanoicacid

In analogy to the procedure for Example 10, 368 mg (0.77 mmol) ofExample 27 are used.

Yield: 269 mg (78%)

¹H-NMR (DMSO-d₆, 300 MHz): δ=0.8 (s, 9H), 1.1 (m, 1H), 1.2 (t, 3H),1.5–1.7 (m, 6H), 2.2 (m, 2H), 2.6 (t, 2H), 2.9 (m, 4H), 3.6 (m, 1H), 7.4(m, 2H), 7.8 (m, 1H), 7.9 (m, 1H), 12.0 (br, 2H) ppm.

Example 292-(3-Aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

1.8 g (5.1 mmol)7-cyclopentyl-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 21A) are dissolved in 100 ml methanol, and 200 mg palladium(10% on charcoal) are added. The mixture is exposed to an hydrogenatmosphere until no more hydrogen is absorbed. Then thepalladium/charcoal is removed by filtration and the filtrate isevaporated to dryness in vacuo. The product is purified bychromatography (flash or column chromatography).

Yield: 1.1 g (67%)

¹H-NMR (400 MHz, CD₃OD): δ=1.27 (t, 3H), 1.60–2.18 (m, 8H), 3.01 (q,2H), 3.63–3.74 (m, 1H), 7.79 (d, 1H), 7.14 (t, 1H), 7.48–7.56 (m, 2H)ppm.

Example 30cis-2-(3-Aminophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one

In analogy to the procedure for Example 29, 3.0 g (71 mmol)cis-7-(4-tert-butylcyclohexyl)-5-ethyl-2-(3-nitrophenyl)imidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 22A) and proportionate amounts of the other reagents are used.

Yield: 300 mg (11%)

¹H-NMR (300 MHz, DMSO-d₆): δ=0.83 (s, 9H), 1.03–1.16 (m, 1H), 1.23 (t,3H), 1.49–1.75 (m, 6H), 2.14–2.23 (m, 2H), 2.89 (q, 2H), 3.50–3.56 (m,1H), 5.30–5.36 (m, 1H), 7.75 (d, 1H), 7.05 (d, 1H), 7.09–7.19 (m, 2H)ppm.

Example 31N-[3-(7-Cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)phenyl]-2,2-dimethylpropanamide

50 mg (0.16 mmol)2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]-triazin-4(3H)-one(Example 29) and 78 mg (0.77 mmol) triethylamine are dissolved in 4 mldichloromethane. 37 mg (0.31 mmol) 2,2-dimethylpropanoyl chloride areadded dropwise. The mixture is stirred for 2 hours at room temperatureand then washed with 1 N potassium hydrogensulfate solution and withsaturated sodium hydrogencarbonate solution. The organic layers aredried and evaporated to dryness in vacuo. The product is purified bychromatography (flash or column chromatography).

Yield: 11 mg (17%)

¹H-NMR (400 MHz, CD₃OD): δ=1.28 (t, 3H), 1.32 (s, 9H), 1.67–2.20 (m,8H), 2.97 (q, 2H), 3.72 (m, 1H), 7.49 (t, 1H), 7.66 (d, 1H), 7.74 (d,1H), 8.15 (s, 1H) ppm.

Example 32N-Benzoyl-N-[3-(7-cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]-triazin-2-yl)phenyl]benzamide

In analogy to the procedure for Example 31, 50 mg (0.15 mmol)2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 29), 43 mg (0.31 mmol) benzoyl chloride and proportionateamounts of the other reagents are used.

Yield: 20 mg (19%)

¹H-NMR (400 MHz, CDCl₃): δ=1.31 (t, 3H), 1.62–2.20 (m, 8H), 3.00 (q,2H), 3.64 (quin., 1H), 7.18 (d, 1H), 7.35–7.97 (m, 12H), 8.09 (d, 1H)ppm.

Example 33cis-N-{3-[7-(4-tert-Butylcyclohexyl)-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-][1,2,4]-triazin-2-yl]phenyl}acetamide

5.0 mg (0.076 mmol) acetic acid, 10 mg (0.076 mmol)1-hydroxy-1H-benzotriazole hydrate and 19 mg (0.19 mmol)4-methylmorpholine are dissolved in dichloromethane. The reactionmixture is cooled down to −10° C., then 15 mg (0.076 mmol)1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride are added.The mixture is stirred for 30 min while warming up nearly to roomtemperature, then it is cooled down again to −10° C. After addition of25 mg (0.064 mmol)cis-2-(3-aminophenyl)-7-(4-tert-butylcyclohexyl)-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 30) the mixture is stirred for 2 hours without further cooling.Then it is washed with 1 N potassium hydrogensulfate solution and withsaturated sodium hydrogencarbonate solution. The organic layers aredried and evaporated to dryness in vacuo. The product is purified bychromatography (flash or column chromatography).

Yield: 20 mg (72%)

¹H-NMR (400 MHz, CD₃OD): δ=0.86 (s, 9H), 1.09–1.20 (m, 1H), 1.29 (t,3H), 1.49–1.68 (m, 4H), 1.71–1.82 (m, 2H), 2.16 (s, 3H), 2.36–2.45 (m,2H), 2.99 (q, 2H), 3.55–3.60 (m, 1H), 7.48 (t, 1H), 7.63 (d, 1H), 7.74(d, 1H), 8.16 (s, 1H) ppm.

Example 342-[3-(Benzylamino)phenyl]-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one

In analogy to the procedure for Example 8, 100 mg (0.31 mmol)2-(3-aminophenyl)-7-cyclopentyl-5-ethylimidazo[5,1-f][1,2,4]triazin-4(3H)-one(Example 29), 52 mg (0.49 mmol) benzaldehyde and proportionate amountsof the other reagents are used.

Yield: 14 mg (10%)

¹H-NMR (400 MHz, CD₃OD): δ=1.28 (t, 3H), 1.69–2.17 (m, 8H), 2.96 (q,2H), 3.62 (quin., 1H), 4.39 (s, 2H), 6.82 (d, 1H), 7.10 (d, 1H), 7.17(s, 1H), 7.18–7.25 (m, 2H), 7.27–7.33 (m, 2H), 7.35–7.41 (m, 2H) ppm.

Example 354-(7-Cyclopentyl-5-ethyl-4-oxo-3,4-dihydroimidazo[5,1-f][1,2,4]triazin-2-yl)benzamide

45 mg (0.12 mmol) of Example 11A are suspended in 10 ml dichloroethane,and 165 mg (1.07 mmol) phosphoroxychloride are added. The mixture isevaporated to dryness in vacuo. The product is purified by preparativeHPLC.

Yield: 4 mg (9%)

LC/MS (A): MS (ESI): 351 (M+H)⁺, retention time 2.84 min.

1. A compound of the general formula (I)

in which A denotes phenylene or pyridinylene, which can be substitutedby 0 to 3 residues selected independently from the group consisting ofhalogen, (C₁–C₄)-alkyl, trifluoromethyl, cyano, nitro, (C₁–C₄)-alkoxyand trifluoromethoxy, R¹ denotes hydroxy or a group of the formula—NR³R⁴, —X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein X denotes a bond, —CH₂—,—CH₂—CH₂— or —CH═CH—, R³ and R⁴ are independently selected from thegroup consisting of hydrogen, (C₁–C₆)-alkyl, (C₃–C₇)-cycloalkyl,(C₁–C₆)-alkanoyl and (C₆–C₁₀)-aroyl, wherein (C₁–C₆)-alkyl can befurther substituted with 0 to 3 substituents selected independently fromthe group consisting of (C₃–C₇)-cycloalkyl and (C₆–C₁₀)-aryl, R⁵ denoteshydrogen or (C₁–C₆)-alkyl, R⁶ and R⁷ are independently selected from thegroup consisting of hydrogen, (C₁–C₆)-alkyl, (C₃–C₇)-cycloalkyl and(C₆–C₁₀)-aryl, or together with the nitrogen atom to which they areattached form a 4- to 7-membered heterocyclic ring which may contain oneadditional ring heteroatom selected from N, O or S, R² denotes(C₃–C₁₀)-cycloalkyl, which is optionally substituted up to two times byresidues selected independently from the group consisting of(C₁–C₆)-alkyl, (C₁–C₆)-alkoxy, hydroxy, halogen, trifluoromethyl andoxo.
 2. A compound according to claim 1, whereby A denotes 1,3- or1,4-phenylene, which can be substituted by 0 to 3 residues selectedindependently from the group consisting of fluoro, chloro, bromo,methyl, trifluoromethyl methoxy, ethoxy and trifluoromethoxy, R¹ denoteshydroxy or a group of the formula —NR³R⁴, —X—C(═O)—OR⁵ or—X—C(═O)—NR⁶R⁷, wherein X denotes a bond, —CH₂—CH₂— or —CH═CH—, R³denotes hydrogen, R⁴ denotes hydrogen, (C₁–C₄)-alkyl or(C₁–C₅)-alkanoyl, wherein (C₁–C₄)-alkyl can be further substituted with0 to 3 substituents selected independently from the group consisting ofcyclopentyl, cyclohexyl or phenyl, R⁵ denotes hydrogen, R⁶ and R⁷ areindependently selected from the group consisting of hydrogen,(C₁–C₄)-alkyl and (C₅–C₆)-cycloalkyl, or together with the nitrogen atomto which they are attached form a 5- to 6-membered heterocyclic ringwhich may contain one additional ring heteroatom selected from N, O orS, R² denotes (C₄–C₇)-cycloalkyl, which is optionally substituted up totwo times by residues independently selected from the group consistingof (C₁–C₄)-alkyl, (C₁–C₄)-alkoxy, hydroxy, fluoro, trifluoromethyl andoxo.
 3. A compound according to claim 1 or 2, whereby A denotes 1,3- or1,4-phenylene, R¹ denotes hydroxy or a group of the formula —NR³R⁴,—X—C(═O)—OR⁵ or —X—C(═O)—NR⁶R⁷, wherein X denotes a bond, R³ denoteshydrogen, R⁴ denotes hydrogen, (C₁–C₄)-alkyl, (C₁–C₅)-alkanoyl,cyclohexylmethyl or benzyl, R⁵ denotes hydrogen, R⁶ denotes hydrogen,methyl or ethyl, R⁷ denotes hydrogen, (C₁–C₄)-alkyl, cyclopentyl orcyclohexyl, or R⁶ and R⁷ together with the nitrogen atom to which theyare attached form a morpholino or piperidino ring, R² denotes(C₄–C₆)-cycloalkyl, which is optionally substituted up to two times byidentical or different (C₁–C₄)-alkyl residues.
 4. A compound accordingto claim 1 or 2, whereby A denotes 1.3- or 1,4-phenylene, R¹ denoteshydroxy or a group of the formula —NR³R⁴, —X—C(═O)—OR⁵ or—X—C(═O)—NR⁶R⁷, wherein X denotes a bond, R³ denotes hydrogen, R⁴denotes hydrogen, (C₁–C₄)-alkyl, (C₁–C₅)-alkanoyl, cyclohexyl methyl orbenzyl, R⁵ denotes hydrogen, R⁶ denotes hydrogen, methyl or ethyl, R⁷denotes hydrogen, (C₁–C₄)-alkyl, cyclopentyl or cyclohexyl, or R⁶ and R⁷together with the nitrogen atom to which they are attached form amorpholino or piperidino ring.
 5. A process for the preparation of acompound according to claim 1, characterized in that a compound of thegeneral formula (IV)

in which A, R¹ and R² are defined as in claim 1, is reacted with adehydrating agent.
 6. Pharmaceutical composition containing one or morecompounds according to claim 1 and a pharmacologically acceptablediluent.
 7. A method for the prevention and treatment of a chronicinflammatory lung disease, comprising administering to a patient in needthereof a therapeutically effective amount of a compound of claim
 1. 8.The method of claim 7, wherein the chronic inflammatory lung disease ischronic obstructive pulmonary disease or asthma.